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Supplementary Figure S4 from Comprehensive Ex Vivo Transposon Mutagenesis Identifies Genes That Promote Growth Factor Independence and Leukemogenesis

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posted on 2023-03-30, 23:48 authored by Yabin Guo, Barrett L. Updegraff, Sunho Park, Deniz Durakoglugil, Victoria H. Cruz, Sarah Maddux, Tae Hyun Hwang, Kathryn A. O'Donnell

Consensus clustering analysis of the top 163 CIS genes in acute lymphocytic leukemia.

Funding

The Cancer Prevention Research Institute of Texas

The American Cancer Society

The Welch Foundation

The Sidney Kimmel Foundation

CPRIT Scholar in Cancer Research and a Kimmel Scholar

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ARTICLE ABSTRACT

Aberrant signaling through cytokine receptors and their downstream signaling pathways is a major oncogenic mechanism underlying hematopoietic malignancies. To better understand how these pathways become pathologically activated and to potentially identify new drivers of hematopoietic cancers, we developed a high-throughput functional screening approach using ex vivo mutagenesis with the Sleeping Beauty transposon. We analyzed over 1,100 transposon-mutagenized pools of Ba/F3 cells, an IL3-dependent pro-B-cell line, which acquired cytokine independence and tumor-forming ability. Recurrent transposon insertions could be mapped to genes in the JAK/STAT and MAPK pathways, confirming the ability of this strategy to identify known oncogenic components of cytokine signaling pathways. In addition, recurrent insertions were identified in a large set of genes that have been found to be mutated in leukemia or associated with survival, but were not previously linked to the JAK/STAT or MAPK pathways nor shown to functionally contribute to leukemogenesis. Forced expression of these novel genes resulted in IL3-independent growth in vitro and tumorigenesis in vivo, validating this mutagenesis-based approach for identifying new genes that promote cytokine signaling and leukemogenesis. Therefore, our findings provide a broadly applicable approach for classifying functionally relevant genes in diverse malignancies and offer new insights into the impact of cytokine signaling on leukemia development. Cancer Res; 76(4); 773–86. ©2015 AACR.

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